While the Gulf war illness displays multiple central nervous system (CNS) impairments, cognitive dysfunction, memory loss, depression and anxiety are the most common symptoms. Intake of the prophylactic drug pyridostigmine bromide (PB), prolonged exposure to pesticides (such as DEET and permethrin), and the combat-related stress during the Persian Gulf War-1 are believed to be the underlying causes of Gulf war illness. Consistent with this supposition, studies in our laboratory using a rat model demonstrate that a combined exposure to low doses of the above chemicals (PB, DEET & Permethrin) and mild stress for 28 days causes considerable impairments in the hippocampus- dependent functions, which include impaired ability for new spatial learning, declined ability for making new memories, and increased depressive- and anxiety- like behavior. Analyses of hippocampal tissues further revealed that the behavioral impairments are linked with greatly declined neurogenesis but mostly intact neuronal cell layers in the hippocampus. Considering the role of hippocampal neurogenesis in learning, memory and mood functions, these findings suggest that a greatly declined neurogenesis likely underlies learning & memory impairments and increased depression & anxiety in Gulf war illness. In this context, strategies that greatly enhance hippocampal neurogenesis appear useful for reversing the cognitive dysfunction and the depression and anxiety observed in Gulf war illness. Indeed, our preliminary studies suggest that administration of antidepressants such as fluoxetine (FLU) or rolipram (ROL) after a combined exposure to chemicals (PB+DEET+Permethrin) and stress has promise for improving the hippocampal neurogenesis as well as cognitive function. Therefore, using the above rat model of Gulf war illness, we propose to rigorously analyze the efficacy of distinct clinically applicable strategies for enhancing the hippocampal neurogenesis & cognitive function, and reversing the depressive & anxiety-like behaviors. In Specific Aim 1, we will test the hypothesis that combined applications of an anti-depressant drug (FLU or ROL) and an antioxidant drug (Curcumin [CUR] or Resveratrol [RESV]; dietary supplements having anti-oxidant, anti-inflammatory, and neurogenesis enhancing properties) greatly enhance hippocampal neurogenesis, cognitive function and mood in the rat model of Gulf war illness. In Specific Aim 2, we will address the hypothesis that combined applications of an anti-depressant drug (FLU or ROL) or an antioxidant drug (CUR or RESV) and physical therapy such as the voluntary physical exercise (PE) greatly boost hippocampal neurogenesis, cognitive function as well as mood in the rat model of Gulf war illness. In both aims, we will first expose rats to the three chemicals (PB, DEET & Permethrin) and mild stress (i.e. 5 minutes of restraint stress) for 28 days and ascertain the extent of cognitive dysfunction and depressive & anxiety- like behaviors. Animals will then receive the treatments as described above and undergo testing at 6- weeks after the conclusion of the treatment for cognitive function and depressive & anxiety-like behavior. Following this, their performance in the behavioral tests will be correlated with the extent of hippocampal neurogenesis, the proliferative behavior of neural stem cells (NSCs), and the pattern of expression of genes related to neurogenesis and to suppression of oxidative stress. The overall research is designed to ascertain the therapeutic efficacy of different treatment approaches. Thus, the studies proposed in this project are highly relevant to the Gulf war RFA (BX-09-014) because, this project utilizes a rat model that simulates the various exposures experienced by the Persian Gulf War-1 veterans and the experiments are focused on developing therapeutic strategies for reversing several CNS impairments associated with Gulf war illness.